The World Wildlife Fund (WWF) divides the Nearctic into four Bioregions, defined as "geographic clusters of ecoregions that may span several habitat types, but have strong biogeographic affinities, particularly at taxonomic levels higher than the species level (genus, family)."

Although North America and South America are presently joined by the Isthmus of Panama, these continents were separated for about 180 million years, and evolved very different plant and animal lineages. When the ancient supercontinent of Pangaea split into two about 180 million years ago, North America remained joined to Eurasia as part of the supercontinent of Laurasia, while South America was part of the supercontinent of Gondwana. North America later split from Eurasia. North America has been joined by land bridges to both Asia and South America since then, which allowed an exchange of plant and animal species between the continents, the Great American Interchange.

A former land bridge across the Bering Strait between Asia and North America allowed many plants and animals to move between these continents, and the Nearctic ecozone shares many plants and animals with the Palearctic. The two ecozones are sometimes included in a single Holarctic ecozone.

Many large animals, or megafauna, including horses, camels, mammoths, mastodonts, ground sloths, sabre-tooth cats (Smilodon), the giant short-faced bear (Arctodus simus), and the cheetah, became extinct in North America at the end of the Pleistocene epoch (ice ages), at the same time the first evidence of humans appeared, in what is called the Holocene extinction event. Previously, it was believed that the megafaunal extinctions were caused by the changing climate, but many scientists now believe that while the climate change contributed to these extinctions, the primary cause was hunting by newly arrived humans or, in the case of some large predators, extinction resulting from prey becoming scarce. The American bison (Bison bison), brown bear or grizzly bear (Ursus arctos), moose or Eurasian elk (Alces alces), and elk or wapiti (Cervus canadensis) entered North America around the same time as the first humans, and expanded rapidly, filling ecological niches left empty by the newly extinct North American megafauna.

Tremarctinae, or short-faced, bears, including the extinct giant short-faced bear (Arctodus simius). The last remaining member of the group is the spectacled bear (Tremarctos ornatus) of South America.